FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer

Narayan, Preeti; Osgood, Christy; Singh, Harpreet; Chiu, Haw-Jyh; Ricks, Tiffany K.; Chow, Edwin; Qiu, Junshan; Song, Pengfei; Yu, Jingyu; Namuswe, Frances; Guiterrez-Lugo, Maria; Hou, Sherry; Pierce, William F.; Goldberg, Kirsten B.; Tang, Shenghui; Amiri‐Kordestani, Laleh; Theoret, Marc R.; Pazdur, Richard; Beaver, Julia A.

doi:10.1158/1078-0432.ccr-20-4557

Cited by 78 publications

(45 citation statements)

References 11 publications

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“…36,37 Following the first FDA approval of trastuzumab emtansine (T-DM1) for HER2-positive breast cancer, trastuzumab deruxtecan has been recently approved for the treatment of adults with unresectable or metastatic HER2-positive breast cancers. 38,39,40 It is possible that adding the bone-specificity to ADCs can improve their efficacy against breast cancer bone metastasis. To test this possibility, we first used pClick conjugation technology to site-specifically couple the monomethyl auristatin E (MMAE) to both wild type antibody Tras and the bone-targeting antibody Tras-CH1/CT with the best anti-cancer activity ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone

Tian

Zhang

et al. 2021

Preprint

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Therapeutic antibodies have gone a long way toward realizing their clinical potential and have become very useful for treating a variety of pathologies. Despite the rapid evolution of therapeutic antibodies, their clinical efficacy in treatment of bone tumors has been hampered by the inadequate pharmacokinetics and poor bone tissue accessibility of these large macromolecules. Here, we show that engineering therapeutic antibodies to include bone-homing peptide sequences dramatically enhances their concentration in the bone metastatic niche, resulting in significantly reduced survival and progression of breast cancer bone metastases. To enhance the bone tumor-targeting ability of engineered antibodies, we introduced varying numbers of a bone-homing peptide into permissive internal sites of the anti-HER2 antibody trastuzumab. Compared to the unmodified antibody, the engineered bone-targeting antibodies have similar pharmacokinetics and in vitro cytotoxic activity against HER2-positive cancer cells, but exhibit improved bone tumor distribution in vivo. Accordingly, in xenograft models of breast cancer metastasis to bone sites, engineered antibodies with enhanced bone specificity exhibit increased inhibition of both initial bone metastases and secondary multi-organ metastases from bone lesions. Furthermore, this engineering strategy is also applied to prepare bone-targeting antibody-drug conjugates with enhanced therapeutic efficacy. These results demonstrate that adding bone-specific targeting to antibody therapy results in robust delivery of therapeutic antibodies to the bone tumor niche. This provides a powerful strategy for overcoming inadequate treatment of bone cancer and the development of potentially acquired resistance to therapy.

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Section: Resultsmentioning

confidence: 99%

Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone

Tian

Zhang

et al. 2021

Preprint

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“…Trastuzumab deruxtecan (DS-8201) was approved by the FDA for the treatment of unresectable or metastatic HER2-positive breast cancer in December 2019 ( Narayan et al, 2021 ). Trastuzumab deruxtecan rarely causes cardiotoxic events, and the most common adverse effects are hematological, including anemia, neutropenia, thrombocytopenia, and leukopenia.…”

Section: Clinical Features Of Cardiotoxicitymentioning

confidence: 99%

Cardiotoxicity of Epidermal Growth Factor Receptor 2-Targeted Drugs for Breast Cancer

Yang¹,

Wang²,

Wang³

et al. 2021

Front. Pharmacol.

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Breast cancer is the most common form of cancer in women and its incidence has been increasing over the years. Human epidermal growth factor receptor 2 (HER2 or ErbB2) overexpression is responsible for 20 to 25% of invasive breast cancers, and is associated with poor prognosis. HER2-targeted therapy has significantly improved overall survival rates in patients with HER2-positive breast cancer. However, despite the benefits of this therapy, its cardiotoxicity is a major concern, especially when HER2-targeted therapy is used in conjunction with anthracyclines. At present, the mechanism of this cardiotoxicity is not fully understood. It is thought that HER2-targeting drugs inhibit HER2/NRG 1 dimer formation, causing an increase in ROS in the mitochondria of cardiomyocytes and inhibiting the PI3K/Akt and Ras/MAPK pathways, resulting in cell apoptosis. Antioxidants, ACE inhibitors, angiotensin II receptor blockers, β-blockers, statins and other drugs may have a cardioprotective effect when used with ErbB2-targeting drugs. NT-proBNP can be used to monitor trastuzumab-induced cardiotoxicity during HER2-targeted treatment and may serve as a biological marker for clinical prediction of cardiotoxicity. Measuring NT-proBNP is non-invasive, inexpensive and reproducible, therefore is worthy of the attention of clinicians. The aim of this review is to discuss the potential mechanisms, clinical features, diagnostic strategies, and intervention strategies related to cardiotoxicity of ErbB2-targeting drugs.

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“…In an attempt to overcome this, current research focuses on the use of less potent cytotoxic drugs, with a lower IC 50 than maytansine or auristatin, such as topoisomerase targeting agents (e.g. camptothecin derivatives), highlighted by the recent FDA approval of trastuzumab deruxtecan (approved 2019), and more recently, Sacituzumab Govitecan, (approved 2021) an ADC which targets Trop2 linked to SN-38, the active metabolite of irinotecan [45][46][47][48].…”

Section: Actively Targeted Nanoparticlesmentioning

confidence: 99%

Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface

Tracey

Smyth

Barelle³

et al. 2021

Biochemical Society Transactions

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Interest in nanomedicines has grown rapidly over the past two decades, owing to the promising therapeutic applications they may provide, particularly for the treatment of cancer. Personalised medicine and ‘smart’ actively targeted nanoparticles represent an opportunity to deliver therapies directly to cancer cells and provide sustained drug release, in turn providing overall lower off-target toxicity and increased therapeutic efficacy. However, the successful translation of nanomedicines from encouraging pre-clinical findings to the clinic has, to date, proven arduous. In this review, we will discuss the use of nanomedicines for the treatment of cancer, with a specific focus on the use of polymeric and lipid nanoparticle delivery systems. In particular, we examine approaches exploring the surface functionalisation of nanomedicines to elicit active targeting and therapeutic effects as well as challenges and future directions for nanoparticles in cancer treatment.

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FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer

Cited by 78 publications

References 11 publications

Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone

Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone

Cardiotoxicity of Epidermal Growth Factor Receptor 2-Targeted Drugs for Breast Cancer

Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface

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